Paliperidone is an active metabolite of risperidone. Risperidone is metabolized by cytochrome P-450 IID6 to produce 9-hydroxy-risperidone also known as paliperidone. EP 196132 B1 and U.S. Pat. No. 4,804,663 describe certain 1,2-benzisoxazol-3-yl derivatives having psychotic and anti-serotonin activity including 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4,1-pyrido-[1,2-a]pyrimidin-4-one (Risperidone) which is a mixed 5-HT2/D2-receptor antagonist and a typical neuroleptic drug. They exemplify the process for the preparation of risperidone, which includes the condensation of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one mono hydrochloride and 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole in presence of N,N-dimethylformamide, sodium carbonate and catalytic amount of potassium iodide. The crude risperidone was crystallized from a mixture of DMF and isopropanol. 9-hydroxyrisperidone, its enantiomeric forms and the C2-20 alkanoic acid esters thereof are described in EP 0,368,388. Said esters are considered to be potentially valuable prodrugs of paliperidone.
Risperidone is a highly potent drug having a relatively narrow therapeutic index. It may produce undesirable side effects on over dosage most notably extrapyramidal side effects such as tardive dyskinesia. The most frequently observed adverse reactions include orthostatic hypotension and dizziness, drowsiness, palpitations, weight gain, erectile dysfunction, and a significant increase in rashes and rhinitis.
Accordingly, an antipsychotic agent having the efficacy of risperidone, but causing fewer side effects, would be desirable. It would be desirable to find a compound that has the advantages of risperidone while providing a more predictable dosage regimen in the patient population and decreasing the chances for drug-drug interactions.
Paliperidone was found to overcome some of the problems associated with risperidone. It possesses a longer elimination half life. It has a potent activity in the treatment of psychotic disorders and other conditions, including those that would benefit from an anti diarrheal, an inhibitor of gastro-esophageal reflux and/or an anti emetic, especially in cancer patients receiving chemotherapy and radiation. It is also used in combating autism, hypertension, vascular disorders, obesity, and the withdrawal symptoms associated with cessation of drinking and smoking. It provides a more predictable dosage regimen in the patient population and decreases the chances of drug-drug interactions by avoiding oxidative metabolism for which the cytochrome P4502D6 enzyme system is required.
A process for the synthesis of paliperidone is described in U.S. Pat. No. 5,158,952 according to scheme-1. The preparation of paliperidone via the intermediate 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one is depicted in the last step of the scheme.

A process for the synthesis of intermediate 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one is also described in U.S. Pat. No. 5,688,799. The processes described in the above publications are lengthy, time consuming and result in low chemical yields, making their application in the industry very difficult.